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  Gene Delivery Systems - Improving Pathways, Efficiency and Stability  
  July 06, 2001

Gene Therapy

 
     
  The Knowledge Foundation, Inc., Washington, DC
December 6 + 7, 2001


Thursday, December 6, 2001

7:45 Registration, Exhibit and Poster Set Up, Coffee and Pastries
8:30 Chairperson's Opening Remarks
James E. Hagstrom, Director of Gene Therapy, Mirus Corporation

Physical/ Mechanical Methods

8:35 Physical Methods for DNA Delivery
Leaf Huang, Ph.D., Center for Pharmacogenetics, University of Pittsburgh
DNA is a macromolecule, which does not readily penetrate cell membranes. Although cationic lipids, polymers and other chemical agents can help delivering DNA into the cells, their modest activity and associated toxicity have presented problems in animal and clinical studies. Various physical methods including electroporation, particle bombardment, ultrasound, and hydrodynamic pressure, have been developed for DNA delivery. When used properly, they are very effective and with minimal toxicity. We shall review some of the recent advancements in this area of non-viral gene therapy.
9:10 Stabilization and Physical Characterization of Nonviral Vectors
Tom Anchordoquy, Asst. Professor of Pharm. Biotechnology, University of Colorado School of Pharmacy, Denver
The instability of nonviral vectors must be circumvented if synthetic vectors are to become a marketable pharmaceutical product. This talk describes progress toward stabilizing nonviral vectors as lyophilized formulations. The assessment of recovery is complicated by the lack of a physical property that is directly correlated with transfection rates. To this end, various analytical methods have been used to better characterize vectors.

9:45 In Vivo Gene Delivery to the Liver Using the Bile Duct
James E. Hagstrom, Director of Gene Therapy,
Mirus Corporation
Liver is one of the most important target tissues for gene therapy given its central role in metabolism (e.g. lipoprotein metabolism in various hypercholesterolemias) and the secretion of circulating proteins (e.g. clotting factors in hemophilia). This talk will highlight recent progress we have made in the use of the bile duct as an effective conduit for obtaining high gene expression in the liver.

10:20 Refreshment Break and Exhibit/Poster Viewing

10:50 Energy-Mediated and Passive Gene Delivery Systems
Evan C. Unger, President & Chief Executive Officer, ImaRx Therapeutics
We are developing a complement of technologies for delivery of genes for gene therapy without the need for viral particles. The acoustically active Aerosomes¨ microbubbles and SonoPorationtm are ultrasound mediated delivery platforms for localized delivery of the therapeutic gene of choice. Fluorogenetm is a liquid perfluorocarbon-containing microbubble with cationically charged lipid shell for gene delivery. Other cationic lipids useful for gene delivery have been developed. Targeting ligands can be incorporated to provide site-specific gene delivery.


Polymers in Gene Delivery

11:25 In Vitro and In Vivo Gene Delivery Mediated by Polyethylenimines
Antoine Kichler, Genethon III, Non-Viral Gene Transfer Group, Evry, France
Polyethylenimines belong to one of the most efficient family of cationic compounds for delivery of plasmid DNA into mammalian cells. With the aim to get a better understanding of the mechanism of action of this potent and versatile polymer, we have studied the ability of PEI to facilitate the escape of DNA from endosomes. Our results show that the efficiency of PEIÕs partially relies on their ability to capture the protons which are transferred into the endosomes during acidification.
12:00 Tumor-Targeted DNA Polyplexes for Cancer Gene Therapy
Ernst Wagner, Professor, Chair, Pharmaceutical Biology - Biotechnology, Center of Drug Research, Department of Pharmacy, Ludwig-Maximilians-Universitat Munich
Tumor targeting has been demonstrated in mouse models with intravenously applied surface-shielded DNA polyplexes, based on polyethylenimine (PEI) and ligands for receptor-mediated endocytosis. Applying the tumor necrosis factor (TNF) alpha gene, tumor necrosis and regression of tumors was observed, without systemic TNF-related side effects.

12:35 Cyclodextrin-Based Polymers for Targeted Delivery of Macromolecular Therapeutics
Suzie J. Hwang, Senior Scientist, Insert Therapeutics, Inc.
Linear, cyclodextrin-based polymers have been shown to be non-immunogenic and well-tolerated at high doses in animals. These polymers are capable of mediating gene delivery in vitro with low toxicity. This talk will highlight our progress in developing these polymers for use as systemic delivery vehicles. Issues that will be addressed include polyplex formulation, stabilization and targeting.

1:10 Luncheon, Sponsored by The Knowledge Foundation, Inc.


Polymers In Gene Delivery II

Chairman: Tom Anchordoquy, Asst. Professor of Pharm. Biotechnology, University of Colorado School of Pharmacy, Denver
2:30 Optimizing the HK Polymer as a Non-Viral Carrier
A. James Mixson, Assistant Professor, Department of Pathology, University of Maryland, Baltimore
We have designed a series of HK polymers to determine the variables that affect transfection efficiency. In the presence of liposomes, the branched polymer with the highest number of histidines, HHK4b, was the most effective at enhancing gene expression in several cell lines. Furthermore, when serum was added to the medium during transfection, the combination of HHK4b and liposomes as a gene-delivery vehicle increased luciferase expression by 400-fold compared to liposomes alone. In contrast to linear HK polymers, the higher branched HHK polymers were effective carriers of plasmids in the absence of liposomes. These studies show that small differences in the composition of HK polymers may affect their ability as carriers.

3:05 Glycotargeted Gene Delivery Systems; Steps Toward the Development of Low Molecular Weight Gene Formulations That Function In Vivo
Kevin G. Rice, Associate Professor, Departments of Pharmaceutics and Medicinal Chemistry, College of Pharmacy, University of Michigan
DNA carriers were synthesized that target the asialoglycoprotein receptor or the mannose receptor in mice. Low molecular weight glycopeptides and polyethylene glycol peptides were prepare and characterized. Add-mixtures of these carries were used to condense DNA and then stabilized by cross-linking. The biodistribution of cross-linked 125I-DNA co-condensates was studied following i.v. dosing in mice and correlated with the level of transient gene expression.

3:40 Improved Delivery of Vectors for Gene Therapy using MagnaporeTM Porous Polymers
Bruce S. Morra, Ph.D., President, C.O.O. and C.F.O., Polygenetics
MagnaporeTM porous polymer microspheres, developed by Polygenetics Inc., may address some of the significant problems still exist in delivering gene therapy vectors. Their unique open architecture has been loaded with a high level of adenovirus vectors and shown to deliver them over an extended period of time. The polymers may also be able to reduce antibody effects and target specific cells.

4:15 Refreshment Break and Exhibit/Poster Viewing


Patent and FDA requirements

4:45 Patentability of Gene Delivery Techniques
Lin J. Hymel, Banner & Witcoff, Ltd.
To obtain a patent in the U.S. an invention must be useful, novel, and non-obvious, and the patent application must describe the invention and teach how to make and use it. Less predictable technologies require more extensive teachings. Current policy requires that patent applications for gene delivery techniques describe actual experiments including data obtained with humans or an animal model.
5:20 The FDA Advisory Committee on Gene Delivery Systems: Proposals and Status
Philip Katz, Partner, Crowell & Moring LLP
The FDA has established an Advisory Committee on the regulation of gene delivery systems. The proposals made by this committee and their status will be discussed. Particular emphasis will be on how gene delivery and gene therapy advances fit into the current regulatory scheme and how they could be affected by proposed changes.

6:00 End of Day One


Friday, December 7, 2001

8:00 Coffee, Pastries and Exhibit/Poster Viewing

Viral Gene Delivery

8:40 Chairperson's Remarks
James E. Hagstrom, Director of Gene Therapy, Mirus Corporation
8:45 Adenoviral, AAV and Lentiviral Vectors and Vascular Gene Therapy
James McArthur, Principal Scientist and Senior Director of Preclinical Biology, Cell Genesys
In the field of vascular biology, replication deficient viral vectors offer the potential to delivery genes to explore questions of vascular biology, correct genetic defects or regulate inappropriate cell growth. We have developed second generation adenoviral vectors that allow the safe genetic modification of blood vessels without inducing vessel dysfunction or vessel occlusion. We have also identified novel anti-proliferative genes that can be delivered with first generation adenoviral vectors to balloon injured vessels to prevent restenosis. To study and gain a better understanding of the interactions of angiogenic and anti-angiogenic factors we have employed AAV and lentiviral vectors to stably genetically modify and express these proteins in animal models. The advantages and disadvantages of these systems in the development of therapeutics in the area of vascular biology will be discussed.

9:20 Adenovector Tissue Selectivity by Design
Tom Wickham, GenVec, Inc.
Current adenovirus vectors are limited in their efficiency and specificity for gene transfer to certain tissues due to the native receptors that they use to enter cells. We have been developing improved adenovirus vectors that permit tissue-specific gene transfer. The coat proteins of these vectors have been genetically modified so that native receptor binding has been ablated and tissue-specific ligands are inserted. These vectors are expected to increase the safety, efficiency, and flexibility of gene transfer for multiple gene therapy applications.

9:55 Refreshment Break and Exhibit/Poster Viewing

10:15 Polymer Based Vectors for Gene Delivery
Leonard W. Seymour, Ph.D., Reader in Molecular Therapy, CRC Institute for Cancer Studies, University of Birmingham, UK
Adenovirus vectors for gene therapy can be surface modified with polymers based on poly[N-(2-hydroxypropyl)methacrylamide] in order to decrease recognition by anti-adenovirus antibodies, and to ablate the normal route of infection via CAR. Chemical linkage of new ligands to the surface of the virus can then endow a new tropism, in order to produce a virus that will infect specifically target cells.

10:50 MVA-BN Viral Vector Systems
Dr. Paul Chaplin, PhD, Director Immunology, Bavarian Nordic
Abstract not available at time of print.

11:25 Lunch on Your Own

12:55 Chairperson's Remarks
Dr. Patrick Fogarty, Tosk, Inc.


DNA Vectors

1:00 Transferring Gene Therapy Success From Flies into Mammals
Dr. Patrick Fogarty, Tosk, Inc.
The P element transposon has been routinely used for gene delivery applications in Drosophila melanogaster for over a decade. This presentation focuses on a modification of this P element vector that enables use in all cell types and species tested to date. In this presentation, data will be shown demonstrating the vectorÕs ease and efficient gene delivery in a variety of vertebrate systems. In addition, the presentation will highlight a novel utility of this vector for high throughput production of transgenic animals in one generation.
1:35 Immune Responses to Plasmid DNA
Ronald K. Scheule, Ph.D., Scientific Director, Gene Transfer Research, Genzyme Corporation
Synthetic vector systems using plasmid DNA are immunostimulatory by virtue of bacterial motifs recognized by the innate immune system of mammals. For genetic disease indications it is most often desirable to minimize this immune activation to achieve the most effective therapy. Eliminating these immune stimulatory motifs from plasmid DNA results in both reduced innate and adaptive immune responses as well as improved persistence of expression.

2:10 From Local to Systemic Gene Therapy - Therapeutic Applications of Synthetic Gene Medicines
Alain Rolland, Pharm.D., Ph.D., Senior Vice President, Preclinical R&D, Valentis, Inc.
This presentation will exemplify the potential of the muscle as a bioreactor to produce proteins for local/regional therapeutic benefit. The intramuscular administration of a Del-1 gene medicine encoding a novel angiogenic factor that increases collateral vessel formation in animal models of limb ischemia will be presented. The prospect of regulating the production of systemic proteins for the treatment of anemia and chronic hepatitis will also be discussed. The ability of the GeneSwitchTM system to regulate the expression of an erythropoietin transgene up to one year after a single intramuscular dose and subsequent regulation of hematocrit in rodents by administration of an antiprogestin inducer will be reported. Finally, the development of a cytokine gene medicine for the systemic therapy of lung cancer will be presented.

2:45 Refreshment Break and Exhibit/Poster Viewing


Liposomes

3:15 Systemic Delivery of Cationic Lipid:pDNA Complexes
Simon Eastman, Senior Scientist, Genzyme Corporation
Systemic delivery of first generation cationic lipid:DNA complexes results in low levels of transgene expression and significant toxicities. In addition, transgene expression is usually not persistent, with expression dropping to non-detectable levels 7 -14 days post-administration. By changing the process by which cationic lipid:DNA complexes are prepared, it is possible to gain a significant enhancement in the measured levels of transgene expression. Use of anti-inflammatory drugs can also result in a significant gain in transgene expression along with a decrease in toxicity. Recent developments in pDNA vectorology have also resulted in significant decreases in toxicity observed following systemic administration of complexes and have greatly increased the duration of expression from non-viral gene therapy vectors. Cationic lipid:DNA complexes can also be redosed, resulting in cumulative increases in transgene expression. These factors combined indicate that systemic
delivery of cationic lipid:DNA complexes may be beneficial for some genetic diseases. We are currently assessing the efficacy of these systems in a number of animal models of disease, such as the Fabry mouse model.
3:50 Tumor-Targeted Systemic p53 Gene Delivery Results in Chemo/Radiosensitization of Tumors
Esther H. Chang, Ph.D., Professor, Departments of Oncology and Otolaryngology, Lombardi Cancer Center, Georgetown University Medical Center
A long-standing goal in gene therapy for cancer is a stable, low toxic, systemic gene delivery system that selectively targets tumor cells, including metastatic disease.
A non viral, ligand-directed, cationic-liposome based, systemic delivery system has been optimized in our laboratory for targeted gene therapy of cancer. This gene delivery system, which homes to tumor cells owing to elevated levels of the transferrin or folate receptor on their surface, is highly efficient and tumor-specific. Delivery of normal p53 via this complex has resulted in sensitization of existing tumors to conventional therapeutic agents leading to long-term elimination of tumors.

4:25 Tumor Targeting Using Drug and Gene Encapsulation Technologies with Proprietary Regulatory DNA Sequences
Teni Boulikas, Ph.D., Founder and CEO,
Regulon, Inc.
We have developed a unique liposome-encapsulation technology for drugs, oligonucleotides, plasmids, peptides, proteins, and other macromolecules. LipoplatinTM, the liposomally-encapsulated form of cisplatin, is preferentially targeted to primary tumors and metastases after i.v. injection and can cross the cell mebrane; Lipoplatin dramatically reduced tumor size in Scid mouse xenografts. LipoVIL12, an encapsulated Semliki Forest virus expressing the gene of IL-12 used for immunotherapy of cancer has very low toxicity; the encapsulated virus is also targeted preferentially to primary tumors as well as their metastases after intravenous or intraperitoneal injection. Tumor targeting is based on the long circulation time of drug or gene carrying vehicles and their extravasation through the vascular endothelium of tumors because of imperfections and leakiness during neoangiogenesis. The same encapsulation technology has been successfully applied to a number of reporter and therapeutic genes (Lipogenes) driven by proprietary tumor-specific regulatory DNA sequences. Unlike other similar liposome formulations, RegulonÕs gene and drug vehicles can cross the cell membrane barrier. Two products, Lipoplatin and LipoVIL12 are in Phase I/II Clinical trials in Europe against seven major human malignancies (lung, breast, prostate, pancreatic, head & neck, melanoma and kidney carcinomas).

5:00 Stabilized Antisense-Lipid Particles: Applications for the Delivery of Antisense and Immunostimulatory Oligonucleotides
Sean Semple, Senior Scientist, Research, Inex Pharmaceuticals Corp.
Stabilized antisense-lipid particles (SALP) were developed as an intravenous delivery system for polynucleotides. These particles entrap oligonucleotides at high efficiencies and drug-to-lipid ratios and are very well tolerated following systemic administration. Specific examples and applications will focus on: (1) the use of SALP for the delivery of antisense oligonucleotides against the c-myc proto-oncogene, and (2) delivery of immunostimulatory CpG oligonucleotides.

5:35 End of Conference

 
 
Organized by: The Knowledge Foundation, Inc.
Invited Speakers: James E. Hagstrom, Leaf Huang, Tom Anchordoquy, Evan C. Unger, Antoine Kichler, Ernst Wagner, Suzie J. Hwang, A. James Mixson, Kevin G. Rice, Bruce S. Morra, Lin J. Hymel, Philip Katz, James McArthur, Tom Wickham, Leonard W. Seymour, Paul Chaplin, Patrick Fogarty, Ronald K. Scheule, Alain Rolland, Simon Eastman, Esther H. Chang, Teni Boulikas, Sean Semple
 
Deadline for Abstracts: none
 
Registration: Registration fee includes lunch on the first day, refreshments and all documentation made available to us by speakers.

Commercial registration: US $1099.
Academic/government registration: US $699.

register online at www.knowledgefoundation.com
or via phone/ fax:
617-232 7400 / 617-232 9171

E-mail: meder@knowledgefoundation.com
 
  Posted by:   Margit Eder  
Host: sdsl-64-7-15-194.dsl.chi.megapath.net
   
 
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